Al Jazeera's Rob Reynolds in Nashville said McCain will probably try to be much more aggressive than he had been in the previous debate in Oxford, Mississippi.
A vice-presidential debate between McCain's running mate, Sarah Palin, and her Democratic rival Joe Biden, had been relatively muted.
Polls judged Obama the winner of the first debate two weeks ago, but Tuesday's debate is being held in a more informal, town hall venue - a favourite setting for McCain and one he used in the party primaries this year and in 2000.
During the debate, moderated by Tom Brokaw, a presenter for NBC news, an audience of around 80 people are being permitted to ask the candidates questions.
Both men will also face several email queries.
McCain's campaign has unleashed a number of attacks on Obama in the last few days as his advisers signalled they wanted to move the debate away from the economy.
The Arizona senator and Palin have criticised Obama for his links to William Ayers, a member of the Weather Underground radical group in the 1960s, and his former minister, Reverend Jeremiah Wright.
Obama has responded by raising questions about McCain's relationship with Charles Keating, a central figure in the US "savings and loan" scandal in the late 1980s and early 1990s that cost taxpayers billions of dollars.
McCain was criticised at the time by a US senate committee for his "poor judgement" over the scandal.
The change in tone during the campaign has raised expectations of an explosive debate.
"In order to change the dynamics of this race, we anticipate that McCain will launch his nastiest attacks and continue to lie about Barack Obama's record," Bill Burton, an Obama spokesman, said.
A supporter asked McCain on Monday: "When are you going to take the gloves off?"
McCain replied: "How about Tuesday night?"